MCP-1/CCR2信号途径介导酒精诱导的乳腺癌血管新生  

MCP-1/CCR2 signaling pathway mediates alcohol-induced angiogenesis in breast cancer

作　　者：季丹 何晓刚[1] 汪刚 罗涛 张露 徐晓丹 徐晓军 李菲菲[1] JI Dan;HE Xiao-gang;WANF Gang;LUO Tao;ZHANG Lu;XU Xiao-dan;XU Xiao-jun;LI Fei-fei(School of Basic Medicine,Anhui Medical University,Hefei 230032,China;Anhui Medical College,Hefei 230061,China;Department of Breast Surgery,First Affiliated Hospital of Anhui Medical University,Hefei 230022,China)

机构地区：[1]安徽医科大学基础医学院,安徽合肥230032 [2]安徽医学高等专科学校,安徽合肥230061 [3]安徽医科大学第一附属医院乳腺外科,安徽合肥230022

出　　处：《中国病理生理杂志》2020年第6期969-976,共8页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.81302319);安徽省教育厅重大研究项目(No.KJ2018ZD018)。

摘　　要：目的:研究单核细胞趋化蛋白1(MCP-1)及其受体CC趋化因子受体2(CCR2)在酒精刺激乳腺癌血管生成中的作用及其机制。方法:建立小鼠饮酒乳腺癌移植瘤模型,免疫组化检测肿瘤组织中MCP-1和CCR2表达与血管标志物血小板内皮细胞黏附分子1(PECAM-1)和血管内皮生长因子(VEGF)表达的相关性。体外建立3D肿瘤-内皮细胞共培养系统观察肿瘤血管新生,检测MCP-1/CCR2信号在酒精介导血管生成中的作用。通过细胞迁移实验检测MCP-1/CCR2是否增加细胞移动而促进脉管形成。结果:饮酒的荷瘤小鼠肿瘤组织中MCP-1和CCR2均高表达,且表达水平和血管新生标志物PECAM-1和VEGF相一致。通过3D肿瘤-内皮细胞共培养系统观察到小鼠乳腺癌E0771细胞和内皮细胞相互作用可促进血管的形成,酒精可以增强此种肿瘤血管新生效应。外源性MCP-1可以促进此种肿瘤血管生成,其受体CCR2抑制剂处理则可以有效抑制酒精刺激的肿瘤血管生成。进一步研究发现MCP-1/CCR2可以增强内皮细胞的迁移能力。结论:MCP-1/CCR2信号途径在酒精刺激乳腺癌血管生成中发挥重要作用,其机制可能是促进了内皮细胞的迁移从而加速了肿瘤脉管新生。AIM:To investigate the role of monocyte chemoattractant protein-1(MCP-1)and its receptor CC chemokine receptor 2(CCR2)in ethanol-promoted breast cancer angiogenesis and the underlying mechanism.METHODS:A mouse model of transplanted breast tumor with moderate alcohol consumption was established.The corre⁃lations between the expression of MCP-1/CCR2 and the expression of angiogenesis markers[platelet endothelial cell adhe⁃sion molecule-1(PECAM-1)and vascular endothelial growth factor(VEGF)]in tumor tissues were examined by immuno⁃histochemistry.In vitro,a 3D tumor-endothelial co-culture system was established to observe tumor angiogenesis and the role of MCP-1/CCR2 signaling pathway in alcohol-mediated angiogenesis.The cell migration ability was detected to clarify whether MCP-1/CCR2 enhanced cell mobility to form new vessels.RESULTS:MCP-1 and CCR2 were both highly ex⁃pressed in the breast tumor tissues of tumor-bearing mice consuming alcohol,and their expression levels were consistent with the angiogenic markers PECAM-1 and VEGF(P<0.05).The interaction between mouse breast cancer E0771 cells and endothelial cells was observed to promote angiogenesis in the 3D tumor-endothelial co-culture system with or without alcohol stimulation.MCP-1 promoted this kind of tumor angiogenesis,while CCR2 antagonist effectively inhibited the tumor angiogenesis and especially blocked alcohol-induced angiogenesis.Activation of MCP-1/CCR2 signaling pathway en⁃hanced the migration ability of endothelial cells.CONCLUSION:The MCP-1/CCR2 signaling pathway plays an impor⁃tant role in promoting the angiogenesis of breast cancer stimulated by alcohol.The mechanism might be that MCP-1 im⁃proves the migration of endothelial cells and then promotes angiogenesis.

关 键 词：酒精 乳腺癌 血管生成 单核细胞趋化蛋白1 CC趋化因子受体2 

分 类 号：R329.21[医药卫生—人体解剖和组织胚胎学] R737.9[医药卫生—基础医学]